The mission of the Neuro-Oncology Program is to improve the standard of care for brain cancers. The Program features a broad portfolio of research initiatives in the general clinical disciplines (medical, radiation and surgical oncology) and in therapeutically relevant scientific areas (e.g. oncolytic viruses, signal transduction, angiogenesis, tumor immunology). For this CCSG renewal, we will focus on astrocytomas ? the most lethal brain tumor of adults and the most common brain tumor of childhood. We have four specific aims: Aim one is to determine why adult gliomas are unresponsive to signal transduction antagonists that are 1) genetically indicated, 2) brain-penetrant, and 3) effective in other cancers. Aim two is to adapt emerging tools of immunotherapy to the treatment of adult gliomas. Our study plan addresses an important unmet need in this area - namely a broader portfolio of antigenic targets for glioma. We will explore a whole exome sequencing approach (NeoVax) that generates synthetic peptide vaccines corresponding to novel open reading frames encoding cell surface proteins on tumor cells. Aim three addresses IDH mutant gliomas in young adults. Our preclinical work, together with early clinical data, suggests that effects of the oncometabolite R-2HG in glioma will, unlike leukemia, not be reversible on a clinically relevant time-scale. Our study plan draws upon new imaging techniques for visualizing R-2HG in IDH mutant glioma patients and a synthetic lethal approach to drug development based upon actionable metabolic changes that arise as a consequence of IDH1 mutation. Aim four is to develop targeted therapeutics for pediatric gliomas. Activating mutations of the serine/threonine protein kinase BRAF are found in 70-75% of pediatric low-grade astrocytomas (PLGAs). Our study plan addresses the unmet need for effective brain-penetrant RAF inhibitors for PLGA. The Program is led by Tracy Batchelor MDMGH and Charles Stiles, PhDDFCI. At the time of the last CCSG renewal in 2011 it received a merit score of ?outstanding to excellent?. There are 94 members in the Program drawn from all seven DF/HCC member institutions. Collectively, the members receive over $31 million per year in cancer-relevant funding. Of this total research support package, $11.6 million is NCI funding and another $8.4M is from other peer-reviewed sources including NINDS (which, in a unique relationship, shares the burden of brain cancer research with NCI). The remaining $12M is from non peer-reviewed sources. One prominent component of the support package is a SPORE/P50 grant on glioma, newly awarded since the last CCSG renewal in 2011. Another important grant is a P01 on pediatric astrocytoma - one of just two P01s, nation-wide focused exclusively on pediatric brain cancer. During the project period, Neuro- Oncology Program members generated over 1,000 publications. Of these, 25% were inter-institutional, 26% were intra-programmatic, and 31% were inter-programmatic collaborations between two or more DF/HCC members. Overall, when counted once, 27% of DF/HCC publications were inter-programmatic collaborations.